Loss of POLE3-POLE4 unleashes replicative gap accumulation upon treatment with PARP inhibitors.
Cell Rep
; 43(5): 114205, 2024 May 28.
Article
em En
| MEDLINE
| ID: mdl-38753485
ABSTRACT
The advent of PARP inhibitors (PARPis) has profoundly changed the treatment landscape of BRCA1/BRCA2-mutated cancers. Despite this, the development of resistance to these compounds has become a major challenge. Hence, a detailed understanding of the mechanisms underlying PARPi sensitivity is crucially needed. Here, we show that loss of the POLE3-POLE4 subunits of DNA polymerase epsilon (Polε) strongly sensitizes cancer cells to PARPis in a Polε level-independent manner. Loss of POLE3-POLE4 is not associated with defective RAD51 foci formation, excluding a major defect in homologous recombination. On the contrary, treatment with PARPis triggers replicative gap accumulation in POLE3-POLE4 knockout (KO) cells in a PRIMPOL-dependent manner. In addition to this, the loss of POLE3-POLE4 further sensitizes BRCA1-silenced cells to PARPis. Importantly, the knockdown of 53BP1 does not rescue PARPi sensitivity in POLE3-POLE4 KO cells, bypassing a common PARPi resistance mechanism and outlining a potential strategy to sensitize cancer cells to PARPis.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Resistencia a Medicamentos Antineoplásicos
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DNA Polimerase III
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DNA Polimerase Dirigida por DNA
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Replicação do DNA
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Inibidores de Poli(ADP-Ribose) Polimerases
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article